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1.  A Novel ERAP2 Haplotype Structure in a Chilean Population: Implications for ERAP2 Protein Expression and Preeclampsia Risk 
Single nucleotide polymorphisms (SNPs) in the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene are associated with preeclampsia (PE) in different populations. rs2549782, a coding variant (N392K) that significantly affects substrate specificity, is in linkage disequilibrium (LD) with rs2248374, a marker SNP associated with ERAP2 protein expression in previously studied populations. As a result of non-sense mediated RNA decay, ERAP2 protein is not expressed from the rs2248374 G allele. We previously reported that the fetal rs2549782 minor G allele is associated with PE in African-Americans, but not Chileans. In this study, we found that rs2549782 was in LD with rs2248374 in African-Americans, but not in Chileans. The unexpected lack of strong LD in Chileans raised the possibility that rs2248374 could be associated with PE in the absence of an association with rs2549782. However, we found no significant association for this allele with PE in Chileans. Chileans homozygous for the rs2248374 G allele did not express 110 kDa ERAP2 protein, consistent with non-sense mediated RNA decay, and carriers of the rs2248374 A allele did. We conclude that the Chilean ERAP2 haplotype structure allows for the expression of the major T allele of rs2549782 encoding 392N, which could impact peptide trimming and antigen presentation. Our discovery of racial differences in genetic structure and association with PE reveal here-to-fore unrecognized complexity of the ERAP2 locus.
doi:10.1002/mgg3.13
PMCID: PMC3769221  PMID: 24040622
ERAP2; preeclampsia; African-Americans; Chileans; haplotype
2.  Sperm-Associated Antigen–17 Gene Is Essential for Motile Cilia Function and Neonatal Survival 
Primary ciliary dyskinesia (PCD), resulting from defects in cilia assembly or motility, is caused by mutations in a number of genes encoding axonemal proteins. PCD phenotypes are variable, and include recurrent respiratory tract infections, bronchiectasis, hydrocephaly, situs inversus, and male infertility. We generated knockout mice for the sperm-associated antigen–17 (Spag17) gene, which encodes a central pair (CP) protein present in the axonemes of cells with “9 + 2” motile cilia or flagella. The targeting of Spag17 resulted in a severe phenotype characterized by immotile nasal and tracheal cilia, reduced clearance of nasal mucus, profound respiratory distress associated with lung fluid accumulation and disruption of the alveolar epithelium, cerebral ventricular expansion consistent with emerging hydrocephalus, failure to suckle, and neonatal demise within 12 hours of birth. Ultrastructural analysis revealed the loss of one CP microtubule in approximately one quarter of tracheal cilia axonemes, an absence of a C1 microtubule projection, and other less frequent CP structural abnormalities. SPAG6 and SPAG16 (CP proteins that interact with SPAG17) were increased in tracheal tissue from SPAG17-deficient mice. We conclude that Spag17 plays a critical role in the function and structure of motile cilia, and that neonatal lethality is likely explained by impaired airway mucociliary clearance.
doi:10.1165/rcmb.2012-0362OC
PMCID: PMC3727877  PMID: 23418344
primary ciliary dyskinesia; axoneme; central pair; Spag17; cilia
3.  Extracellular Matrix Dynamics and Fetal Membrane Rupture 
Reproductive Sciences  2013;20(2):140-153.
The extracellular matrix (ECM) plays an important role in determining cell and organ function: (1) it is an organizing substrate that provides tissue tensile strength; (2) it anchors cells and influences cell morphology and function via interaction with cell surface receptors; and (3) it is a reservoir for growth factors. Alterations in the content and the composition of the ECM determine its physical and biological properties, including strength and susceptibility to degradation. The ECM components themselves also harbor cryptic matrikines, which when exposed by conformational change or proteolysis have potent effects on cell function, including stimulating the production of cytokines and matrix metalloproteinases (MMPs). Collectively, these properties of the ECM reflect a dynamic tissue component that influences both tissue form and function. This review illustrates how defects in ECM synthesis and metabolism and the physiological process of ECM turnover contribute to changes in the fetal membranes that precede normal parturition and contribute to the pathological events leading to preterm premature rupture of membranes (PPROM).
doi:10.1177/1933719111424454
PMCID: PMC3826277  PMID: 22267536
extracellular matrix; PPROM; matrix metalloproteinase; collagens; fibronectin; amnion; chorion
4.  A novel ERAP2 haplotype structure in a Chilean population: implications for ERAP2 protein expression and preeclampsia risk 
Single nucleotide polymorphisms (SNPs) in the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene are associated with preeclampsia (PE) in different populations. rs2549782, a coding variant (N392K) that significantly affects substrate specificity, is in linkage disequilibrium (LD) with rs2248374, a marker SNP associated with ERAP2 protein expression in previously studied populations. As a result of nonsense-mediated RNA decay, ERAP2 protein is not expressed from the rs2248374 G allele. We previously reported that the fetal rs2549782 minor G allele is associated with PE in African-Americans, but not in Chileans. In this study, we found that rs2549782 was in LD with rs2248374 in African-Americans, but not in Chileans. The unexpected lack of strong LD in Chileans raised the possibility that rs2248374 could be associated with PE in the absence of an association with rs2549782. However, we found no significant association for this allele with PE in Chileans. Chileans homozygous for the rs2248374 G allele did not express 110 kDa ERAP2 protein, consistent with nonsense-mediated RNA decay, and carriers of the rs2248374 A allele did. We conclude that the Chilean ERAP2 haplotype structure allows for the expression of the major T allele of rs2549782 encoding 392N, which could impact peptide trimming and antigen presentation. Our discovery of racial differences in genetic structure and association with PE reveal heretofore unrecognized complexity of the ERAP2 locus.
doi:10.1002/mgg3.13
PMCID: PMC3769221  PMID: 24040622
African-Americans; Chileans; ERAP2; haplotype; preeclampsia
5.  Catechol-O-Methyltransferase (COMT) Single Nucleotide Polymorphisms and Haplotypes Are Not Major Risk Factors for Polycystic Ovary Syndrome 
Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 5–8% of reproductive age women. The primary features of PCOS are hyperandrogenemia, chronic anovulation and infertility. It has been suggested that defects in ovarian steroid metabolism contribute to the follicular growth arrest and abnormal production of ovarian steroid hormones that are characteristic of PCOS. 2-methoxyestradiol (2-ME) is formed by the action of catechol-O-methyltransferase (COMT) on 2-hydroxyestradiol. COMT expression is increased in the follicles and ovarian stroma of women with PCOS. Moreover, 2-ME decreases granulosa cell proliferation and steroidogenesis, raising the possibility that ovarian dysfunction associated with PCOS is due, in part, to increased synthesis of 2-ME resulting from increased COMT activity. Four single-nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4818, rs4680) in the COMT gene characterize haplotypes, which are associated with large variations in COMT enzymatic activity. The aim of this study was to determine whether individual COMT SNPs and the COMT haplotypes are associated with PCOS using a family-based test of association and linkage. Additionally, we examined the relationships between COMT SNPs and haplotypes with quantitative variables usually assessed in the evaluation of women with PCOS. There were no significant correlations between genotype and total testosterone, non-SHBG bound testosterone and BMI. However, we found that the prolactin level in women with PCOS varied significantly with COMT haplotype, and suggest that this association reflects a genetic factor influencing the stress response. Our findings suggest that common variants and haplotypes of the COMT gene are not major contributors to risk for PCOS, but that COMT genotype may influence prolactin levels.
doi:10.1016/j.mce.2011.11.022
PMCID: PMC3264817  PMID: 22178088
Catechol-O-Methyltransferase; COMT; polycystic ovary syndrome; prolactin5
6.  TYPE 2 DIABETES SUSCEPTIBILITY SNPS ARE NOT ASSOCIATED WITH PCOS 
Fertility and sterility  2011;95(8):2538-2541.e6.
Two cohorts of women with PCOS (400 probands and affected sisters in 365 families and a case-control group including 395 women with PCOS and 171 healthy women with regular menstrual cycles) were studied to determine whether SNPs identified as susceptibility loci in genome-wide association studies of type 2 diabetes are also associated with PCOS. None of the 18 allelic variants in ten genes previously shown to be associated with type 2 diabetes were found to be associated with PCOS, but some were associated with indices of beta cell function.
doi:10.1016/j.fertnstert.2011.02.050
PMCID: PMC3124609  PMID: 21444075
7.  Medicaid and Preterm Births in Virginia: An Analysis of Recent Outcomes 
Journal of Women's Health  2010;19(11):1969-1975.
Abstract
Objectives
The study objectives were to evaluate adequacy of prenatal care and risk for preterm birth among Medicaid clients in Virginia and to determine if payment method is associated with the risk of preterm birth.
Methods
Birth certificate data for the Commonwealth of Virginia for 2007 and 2008 were linked with Medicaid claims data. Analysis was limited to singleton births. Three payment methods were evaluated: private insurance, self-pay, and Medicaid. The prevalence of preterm birth for each level of prenatal care defined by the Kotelchuck prenatal care index was assessed for each payment method. Unconditional logistic regression modeling was used to assess the association between payment method and preterm birth risk while controlling for known preterm birth risk factors.
Results
Preterm birth prevalences (95% confidence interval [CI]) for the different payment methods were 7.9% (4.79-8.07) for the privately insured, 10.1% (9.57-10.60) for the self-pay group, and 10.2% (9.95-10.45) for Medicaid recipients. Compared with those with private insurance, women on Medicaid had an adjusted odds ratio (OR) for preterm birth (95% CI) of 0.99 (0.94-1.03). Self-pay mothers had a 32% increase in the odds of preterm birth relative to the privately insured. All payment groups show a trend toward significant reduction in preterm birth prevalence as adequacy of prenatal care improved from inadequate to adequate. Medicaid enrollees had a high prevalence of known risk factors, including smoking and illicit drug use and cervical insufficiency.
Conclusions
When known risk factors have been controlled, preterm birth risk for Medicaid enrollees did not differ significantly from the privately insured.
doi:10.1089/jwh.2010.1955
PMCID: PMC2971635  PMID: 20831442
8.  Medicaid and Preterm Birth and Low Birth Weight: The Last Two Decades 
Journal of Women's Health  2010;19(3):443-451.
Abstract
Objectives
To determine if (1) birth outcomes among women on Medicaid differ significantly from outcomes of those with private insurance, after controlling for known risk factors, and (2) enhanced prenatal care influences care use and birth outcomes.
Methods
This is a review of studies published between 1989 and 2009 that examined birth outcomes (1) between women on Medicaid and those with private insurance and (2) among Medicaid enrollees who received comprehensive prenatal care.
Results
When corrected for risk variables, birth outcomes are not different between private insurance and Medicaid patients. The impact of comprehensive prenatal care programs on birth outcomes varies across states and regions.
Conclusions
There is a need for critical evaluation of comprehensive programs in a regional and state context to determine opportunities for improvement.
doi:10.1089/jwh.2009.1602
PMCID: PMC2867587  PMID: 20141370
9.  A Single Nucleotide Polymorphism in the Promoter of the LOXL1 Gene and Its Relationship to Pelvic Organ Prolapse and Preterm Premature Rupture of Membranes 
Pelvic organ prolapse (POP) and preterm premature rupture of the membranes (PPROM), two conditions which have in common weakening of the tensile strength of tissues, are thought to be caused, in part, by abnormal extracellular matrix synthesis and/or catabolism. We identified a new single nucleotide polymorphism (SNP) (NT_010194(LOXL1):g.45008784A>C) in the promoter of the LOXL1 gene, which is essential for elastin synthesis. Promoter studies showed that the minor “C” allele had significantly greater activity than the major “A” allele. Case-control studies examined the association of the alleles of this SNP with POP and PPROM. When comparing allele frequencies and genotypes in POP cases versus controls, no significant associations were found. A case-control study conducted in African-American neonates also found no significant associations between the promoter alleles and PPROM. We conclude that a functional SNP exists in the promoter region of LOXL1. Association studies suggest that the promoter SNP does not contribute significantly to risk of POP or PPROM.
doi:10.1177/1933719108330567
PMCID: PMC2668743  PMID: 19182211
Lysyl oxidase-like 1; pelvic organ prolapse; preterm premature rupture of membranes; elastin
10.  Connective Tissue and Related Disorders and Preterm Birth: Clues to Genes Contributing to Prematurity 
Placenta  2009;30(3):207-215.
To identify candidate genes contributing to preterm birth, we examined the existing literature on the association between known disorders of connective tissue synthesis and metabolism and related diseases and prematurity. Our hypothesis was that abnormal matrix metabolism contributes to prematurity by increasing risk of preterm premature rupture of membranes (PPROM) and cervical incompetence. Based on this review, we identified gene mutations inherited by the fetus that could predispose to preterm birth as a result PPROM. The responsible genes include COL5A1, COL5A2, COL3A1, COL1A1, COL1A2, TNXB, PLOD1, ADAMTS2, CRTAP, LEPRE1 and ZMPSTE24. Marfan syndrome, caused by FBN1 mutations, and polymorphisms in the COL1A1 and TGFB1 genes have been associated with cervical incompetence. We speculate that an analysis of sequence variation at the loci noted above will reveal polymorphisms that may contribute to susceptibility to PPROM in the general population.
doi:10.1016/j.placenta.2008.12.007
PMCID: PMC2673455  PMID: 19152976
Connective tissue; Genes; Preterm Birth; PPROM; Cervical incompetence
11.  Expression Profile of Male Germ Cell-Associated Genes in Mouse Embryonic Stem Cell Cultures Treated with All-Trans Retinoic Acid and Testosterone 
Cells that morphologically and functionally resemble male germ cells can be spontaneously derived from ES cells. However, this process is inefficient and unpredictable suggesting that the expression pattern of male germ cell associated genes during spontaneous ES cell differentiation does not mimic the in vivo profiles of the genes. Thus, in the present study, the temporal expression profile of genes expressed at different stages of male germ cell development was examined in differentiating ES cells. The effect of all-trans retinoic acid (RA) which is a known inducer of primordial germ cell (PGC) proliferation/survival in vitro and testosterone which is required for spermatogenesis in vivo on the expression of these genes was also determined. Each of the 12 genes analyzed exhibited one of four temporal expression patterns in untreated differentiating ES cells: progressively decreased (Dpp3a, Sycp3, Msy2), initially low and then increased (Stra8, Sycp1, Dazl, Act, Prm1), initially decreased and then increased (Piwil2, Tex14), or relatively unchanged (Akap3, Odf2). RA-treated cells exhibited increased expression of Stra8, Dazl, Act, and Prm1 and suppressed expression of Dpp3a compared to untreated controls. Furthermore, testosterone increased expression of Stra8 while the combination of RA and testosterone synergistically increased expression of Act. Our findings establish a comprehensive profile of male germ cell gene expression during spontaneous differentiation of murine ES cells and describe the capacity of RA and testosterone to modulate the expression of these genes. Furthermore, these data represent an important first step in designing a plausible directed differentiation protocol for male germ cells.
doi:10.1002/mrd.20925
PMCID: PMC2664383  PMID: 18425777
Spermatogenesis; Gene Expression Profiling; Real-Time PCR; Embryoid Bodies
12.  Genetic Contributions to Disparities in Preterm Birth 
Pediatric research  2009;65(1):1-9.
Ethnic disparity in preterm delivery between African Americans and European Americans has existed for decades, and is likely the consequence of multiple factors, including socioeconomic status, access to care, environment, and genetics. This review summarizes existing information on genetic variation and its association with preterm birth in African Americans. Candidate gene-based association studies, in which investigators have evaluated particular genes selected primarily because of their potential roles in the process of normal and pathological parturition, provide evidence that genetic contributions from both mother and fetus account for some of the disparity in preterm births. To date, most attention has been focused on genetic variation in pro- and anti-inflammatory cytokine genes and their respective receptors. These genes, particularly the pro-inflammatory cytokine genes and their receptors, are linked to matrix metabolism since these cytokines increase expression of matrix degrading metalloproteinases. However, the role that genetic variants that are different between populations play in preterm birth cannot yet be quantified. Future studies based on genome wide association or admixture mapping may reveal other genes that contribute to disparity in prematurity.
doi:10.1203/PDR.0b013e31818912e7
PMCID: PMC2651992  PMID: 18787421
Genes; racial/ethnic disparities; preterm birth
13.  Otitis Media in Sperm-Associated Antigen 6 (Spag6)-Deficient Mice 
PLoS ONE  2014;9(11):e112879.
Mammalian SPAG6 protein is localized to the axoneme central apparatus, and it is required for normal flagella and cilia motility. Recent studies demonstrated that the protein also regulates ciliogenesis and cilia polarity in the epithelial cells of brain ventricles and trachea. Motile cilia are also present in the epithelial cells of the middle ear and Eustachian tubes, where the ciliary system participates in the movement of serous fluid and mucus in the middle ear. Cilia defects are associated with otitis media (OM), presumably due to an inability to efficiently transport fluid, mucus and particles including microorganisms. We investigated the potential role of SPAG6 in the middle ear and Eustachian tubes by studying mice with a targeted mutation in the Spag6 gene. SPAG6 is expressed in the ciliated cells of middle ear epithelial cells. The orientation of the ciliary basal feet was random in the middle ear epithelial cells of Spag6-deficient mice, and there was an associated disrupted localization of the planar cell polarity (PCP) protein, FZD6. These features are associated with disordered cilia orientation, confirmed by scanning electron microscopy, which leads to uncoordinated cilia beating. The Spag6 mutant mice were also prone to develop OM. However, there were no significant differences in bacterial populations, epithelial goblet cell density, mucin expression and Eustachian tube angle between the mutant and wild-type mice, suggesting that OM was due to accumulation of fluid and mucus secondary to the ciliary dysfunction. Our studies demonstrate a role for Spag6 in the pathogenesis of OM in mice, possibly through its role in the regulation of cilia/basal body polarity through the PCP-dependent mechanisms in the middle ear and Eustachian tubes.
doi:10.1371/journal.pone.0112879
PMCID: PMC4231073  PMID: 25393619
14.  Reassessing the Impact of Smoking on Preeclampsia/Eclampsia: Are There Age and Racial Differences? 
PLoS ONE  2014;9(10):e106446.
Objective
To investigate the association between cigarette use during pregnancy and pregnancy-induced hypertension/preeclampsia/eclampsia (PIH) by maternal race/ethnicity and age.
Methods
This retrospective cohort study was based on the U.S. 2010 natality data. Our study sample included U.S. women who delivered singleton pregnancies between 20 and 44 weeks of gestation without major fetal anomalies in 2010 (n = 3,113,164). Multivariate logistic regression models were fit to estimate crude and adjusted odds ratios and the corresponding 95% confidence intervals.
Results
We observed that the association between maternal smoking and PIH varied by maternal race/ethnicity and age. Compared with non-smokers, reduced odds of PIH among pregnant smokers was only evident for non-Hispanic white and non-Hispanic American Indian women aged less than 35 years. Non-Hispanic Asian/Pacific Islander women who smoked during pregnancy had increased odds of PIH regardless of maternal age. Non-Hispanic white and non-Hispanic black women 35 years or older who smoked during pregnancy also had increased odds of PIH.
Conclusion
Our study findings suggest important differences by maternal race/ethnicity and age in the association between cigarette use during pregnancy and PIH. More research is needed to establish the biologic and social mechanisms that might explain the variations with maternal age and race/ethnicity that were observed in our study.
doi:10.1371/journal.pone.0106446
PMCID: PMC4206265  PMID: 25337852
15.  An Emerging Mycoplasma Associated with Trichomoniasis, Vaginal Infection and Disease 
PLoS ONE  2014;9(10):e110943.
Humans are colonized by thousands of bacterial species, but it is difficult to assess the metabolic and pathogenic potential of the majority of these because they have yet to be cultured. Here, we characterize an uncultivated vaginal mycoplasma tightly associated with trichomoniasis that was previously known by its 16S rRNA sequence as “Mnola.” In this study, the mycoplasma was found almost exclusively in women infected with the sexually transmitted pathogen Trichomonas vaginalis, but rarely observed in women with no diagnosed disease. The genomes of four strains of this species were reconstructed using metagenome sequencing and assembly of DNA from four discrete mid-vaginal samples, one of which was obtained from a pregnant woman with trichomoniasis who delivered prematurely. These bacteria harbor several putative virulence factors and display unique metabolic strategies. Genes encoding proteins with high similarity to potential virulence factors include two collagenases, a hemolysin, an O-sialoglycoprotein endopeptidase and a feoB-type ferrous iron transport system. We propose the name “Candidatus Mycoplasma girerdii” for this potential new pathogen.
doi:10.1371/journal.pone.0110943
PMCID: PMC4206474  PMID: 25337710
16.  Sperm-Associated Antigen 6 (SPAG6) Deficiency and Defects in Ciliogenesis and Cilia Function: Polarity, Density, and Beat 
PLoS ONE  2014;9(10):e107271.
SPAG6, an axoneme central apparatus protein, is essential for function of ependymal cell cilia and sperm flagella. A significant number of Spag6-deficient mice die with hydrocephalus, and surviving males are sterile because of sperm motility defects. In further exploring the ciliary dysfunction in Spag6-null mice, we discovered that cilia beat frequency was significantly reduced in tracheal epithelial cells, and that the beat was not synchronized. There was also a significant reduction in cilia density in both brain ependymal and trachea epithelial cells, and cilia arrays were disorganized. The orientation of basal feet, which determines the direction of axoneme orientation, was apparently random in Spag6-deficient mice, and there were reduced numbers of basal feet, consistent with reduced cilia density. The polarized epithelial cell morphology and distribution of intracellular mucin, α-tubulin, and the planar cell polarity protein, Vangl2, were lost in Spag6-deficient tracheal epithelial cells. Polarized epithelial cell morphology and polarized distribution of α-tubulin in tracheal epithelial cells was observed in one-week old wild-type mice, but not in the Spag6-deficient mice of the same age. Thus, the cilia and polarity defects appear prior to 7 days post-partum. These findings suggest that SPAG6 not only regulates cilia/flagellar motility, but that in its absence, ciliogenesis, axoneme orientation, and tracheal epithelial cell polarity are altered.
doi:10.1371/journal.pone.0107271
PMCID: PMC4204823  PMID: 25333478
17.  Fetal and Maternal Genes’ Influence on Gestational Age in a Quantitative Genetic Analysis of 244,000 Swedish Births 
American Journal of Epidemiology  2013;178(4):543-550.
Although there is increasing evidence that genetic factors influence gestational age, it is unclear to what extent this is due to fetal and/or maternal genes. In this study, we apply a novel analytical model to estimate genetic and environmental contributions to pregnancy history records obtained from 165,952 Swedish families consisting of offspring of twins, full siblings, and half-siblings (1987–2008). Results indicated that fetal genetic factors explained 13.1% (95% confidence interval (CI): 6.8, 19.4) of the variation in gestational age at delivery, while maternal genetic factors accounted for 20.6% (95% CI: 18.1, 23.2). The largest contribution to differences in the timing of birth were environmental factors, of which 10.1% (95% CI: 7.0, 13.2) was due to factors shared by births of the same mother, and 56.2% (95% CI: 53.0, 59.4) was pregnancy specific. Similar models fit to the same data dichotomized at clinically meaningful thresholds (e.g., preterm birth) resulted in less stable parameter estimates, but the collective results supported a model of homogeneous genetic and environmental effects across the range of gestational age. Since environmental factors explained most differences in the timing of birth, genetic studies may benefit from understanding the specific effect of fetal and maternal genes in the context of these yet-unidentified factors.
doi:10.1093/aje/kwt005
PMCID: PMC3736752  PMID: 23568591
environment; fetal genes; gestational age; maternal genes; preterm birth; twins
18.  DNA Methylation is Altered in Maternal Blood Vessels of Women With Preeclampsia 
Reproductive Sciences  2012;19(12):1332-1342.
We analyzed 27 578 CpG sites that map to 14 495 genes in omental arteries of normal pregnant and preeclamptic women for DNA methylation status using the Illumina platform. We found 1685 genes with a significant difference in DNA methylation at a false discovery rate of <10% with many inflammatory genes having reduced methylation. Unsupervised hierarchical clustering revealed natural clustering by diagnosis and methylation status. Of the genes with significant methylation differences, 236 were significant at a false discovery rate of <5%. When data were analyzed more stringently to a false discovery rate of <5% and difference in methylation of >0.10, 65 genes were identified, all of which showed reduced methylation in preeclampsia. When these genes were mapped to gene ontology for molecular functions and biological processes, 75 molecular functions and 149 biological processes were overrepresented in the preeclamptic vessels. These included smooth muscle contraction, thrombosis, inflammation, redox homeostasis, sugar metabolism, and amino acid metabolism. We speculate that reduced methylation may contribute to the pathogenesis of preeclampsia and that alterations in DNA methylation resulting from preeclampsia may increase maternal risk of cardiovascular disease later in life.
doi:10.1177/1933719112450336
PMCID: PMC4046447  PMID: 22902744
preeclampsia; DNA methylation; epigenetics; omental blood vessels; inflammation.
20.  Sex Hormone-Binding Globulin Genetic Variation: Associations with Type 2 Diabetes Mellitus and Polycystic Ovary Syndrome 
Minerva endocrinologica  2010;35(4):271-280.
Sex hormone-binding globulin (SHBG) is the primary plasma transport protein for sex steroid hormones and regulates the bioavailability of these hormones to target tissues. The gene encoding SHBG is complex and any of several polymorphisms in SHBG have been associated with alterations in circulating SHBG levels.
Epidemiological studies have revealed that low plasma SHBG levels are an early indicator of insulin resistance and predict the development of type 2 diabetes mellitus (T2DM) in both men and women. Although associations between low SHBG levels and risk of diabetes could be explained by the observation that elevations in insulin suppress hepatic SHBG production, recent studies documenting that the transmission of SHBG-altering polymorphisms are associated with risk of T2DM suggest that SHBG may have a more direct physiologic role in glucose homeostasis. However, the exact mechanism(s) underlying this association is not known.
Non-diabetic women with the polycystic ovary syndrome (PCOS), a common endocrine disorder that is associated with insulin resistance, similarly demonstrate lower levels of SHBG. In light of studies investigating polymorphisms in SHBG and T2DM, our group and others have hypothesized that SHBG may represent a candidate gene for PCOS. In this manuscript, we review studies investigating the association between SHBG polymorphisms and PCOS. In summary, multiple studies in women with PCOS confirm that certain genetic polymorphisms are associated with circulating SHBG levels, but they are not consistently associated with PCOS per se.
PMCID: PMC3683392  PMID: 21178921
genetic polymorphisms; polycystic ovary syndrome; sex hormone binding globulin; type 2 diabetes mellitus
21.  REDUCED METHYLATION OF THE THROMBOXANE SYNTHASE GENE IS CORRELATED WITH ITS INCREASED VASCULAR EXPRESSION IN PREECLAMPSIA 
Hypertension  2012;59(6):1249-1255.
Preeclampsia is characterized by increased thromboxane and decreased prostacyclin levels, which predate symptoms, and can explain some of the clinical manifestations of preeclampsia, including hypertension and thrombosis. In this study, we examined DNA methylation of the promoter region of the thromboxane synthase gene (TBXAS1) and the expression of thromboxane synthase in systemic blood vessels of normal pregnant and preeclamptic women. Thromboxane synthase is responsible for the synthesis of thromboxane A2, a potent vasoconstrictor and activator of platelets. We also examined the effect of experimentally induced DNA hypomethylation on the expression of thromboxane synthase in a neutrophil-like cell line (HL-60 cells), and in cultured vascular smooth muscle and endothelial cells. We found that DNA methylation of the TBXAS1 promoter was decreased, and thromboxane synthase expression was increased in omental arteries of preeclamptic women as compared to normal pregnant women. Increased thromboxane synthase expression was observed in vascular smooth muscles cells, endothelial cells and infiltrating neutrophils. Experimentally induced DNA hypomethylation only increased expression of thromboxane synthase in the neutrophil-like cell line, whereas tumor necrosis factor-α, a neutrophil product, increased its expression in cultured vascular smooth muscle cells. Our study suggests that epigenetic mechanisms and release of tumor necrosis factor-α by infiltrating neutrophils could contribute to the increased expression of thromboxane synthase in maternal systemic blood vessels, contributing to the hypertension and coagulation abnormalities associated with preeclampsia.
doi:10.1161/HYPERTENSIONAHA.111.188730
PMCID: PMC3355228  PMID: 22493072
preeclampsia; DNA methylation; thromboxane synthase; epigenetics; omental blood vessels; thromboxane A2
22.  The Interaction Effect of Bacterial Vaginosis and Periodontal Disease on the risk of Preterm Delivery 
American journal of perinatology  2011;29(5):347-352.
Objective
To determine if coexistence of periodontal disease (PD) and bacterial vaginosis (BV) is synergistic on the risk of spontaneous preterm delivery (sPTD).
Study Design
Secondary analysis of a prospective cohort study. Women were screened 6–20 weeks gestation for PD and BV. Groups were defined by presence of BV and stratified on PD. The primary outcome was sPTD <37 weeks gestation. Univariable, stratified and multivariable analyses were performed to estimate the main and interaction effects of BV and PD on sPTD.
Results
Of 1453 women screened, 792 (54.5%) were diagnosed with BV. Neither women with BV in the first trimester nor PD were at higher risk of sPTD (risk ratio (RR) for BV 1.1, 95% confidence interval (CI) 0.8–1.5, RR for PD 0.9, 95% CI 0.7–1.3). The interaction between BV and PD did not statistically significantly impact the odds of sPTD.
Conclusions
Coexistence of PD and BV did not have a synergistic effect on sPTD.
doi:10.1055/s-0031-1295644
PMCID: PMC3613845  PMID: 22105437
bacterial vaginosis; periodontal disease; preterm delivery
23.  Replication of Association of DENND1A and THADA Variants with Polycystic Ovary Syndrome in European Cohorts 
Journal of medical genetics  2011;49(2):90-95.
Background
Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterized by hyperandrogenemia and irregular menses. A recent genome wide association study of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinizing hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined.
Methods/Results
We tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European-derived PCOS cohorts (Cohort A = 939 cases and 957 controls; Cohort B = 535 cases and 845 controls). Cases fulfilled the NICHD criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in our cohort (pcombined cohorts=10−8 ); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. We had greater than 80% power to detect an effect of similar size as was observed by Chen et al. for DENND1A and THADA but reduced power (at <40%) for LHCGR at p=0.0001. We had sufficient power (57-88%) for LHCGR at p=0.01.
Conclusions
At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European-derived populations, and therefore likely to be important in the etiology of PCOS regardless of ethnicity. Our analysis of the LHCGR gene was not sufficiently powered to detect modest effects.
doi:10.1136/jmedgenet-2011-100427
PMCID: PMC3536488  PMID: 22180642
PCOS; DENND1A; THADA; genome-wide association study
24.  Sex Hormone-Binding Globulin and Type 2 Diabetes Mellitus 
Sex hormone-binding globulin (SHBG) has emerged as one of the multiple genetic and environmental factors that potentially contribute to the pathophysiology of Type 2 diabetes mellitus (T2DM). In addition to epidemiologic studies demonstrating a consistent relationship between decreased levels of serum SHBG and incident T2DM, recent genetic studies also reveal that transmission of specific polymorphisms in the SHBG gene influence risk of T2DM. On the molecular level, elucidation of the multiple interactions between SHBG and its receptors in various target tissues, suggest physiologic roles for SHBG that are more complex than the simple transport of sex hormones in serum. Taken together, these data provide support for an expanded role of SHBG in the pathophysiology of insulin resistance and T2DM.
doi:10.1016/j.tem.2011.09.005
PMCID: PMC3351377  PMID: 22047952
genetic polymorphisms; sex hormone binding globulin; type 2 diabetes mellitus
25.  Cholesterol Side-Chain Cleavage Gene Expression in Theca Cells: Augmented Transcriptional Regulation and mRNA Stability in Polycystic Ovary Syndrome 
PLoS ONE  2012;7(11):e48963.
Hyperandrogenism is characteristic of women with polycystic ovary syndrome (PCOS). Ovarian theca cells isolated from PCOS follicles and maintained in long-term culture produce elevated levels of progestins and androgens compared to normal theca cells. Augmented steroid production in PCOS theca cells is associated with changes in the expression of genes for several steroidogenic enzymes, including CYP11A1, which encodes cytochrome P450 cholesterol side-chain cleavage. Here, we further examined CYP11A1 gene expression, at both the transcriptional and post-transcriptional level in normal and PCOS theca cells propagated in long-term culture utilizing quantitative RT-PCR, functional promoter analyses, and mRNA degradation studies. The minimal element(s) that conferred increased basal and cAMP-dependent CYP11A1 promoter function were determined. CYP11A1 mRNA half-life in normal and PCOS theca cells was compared. Results of these cumulative studies showed that basal and forskolin stimulated steady state CYP11A1 mRNA abundance and CYP11A1 promoter activity were increased in PCOS theca cells. Deletion analysis of the CYP11A1 promoter demonstrated that augmented promoter function in PCOS theca cells results from increased basal regulation conferred by a minimal sequence between −160 and −90 bp of the transcriptional start site. The transcription factor, nuclear factor 1C2, was observed to regulate basal activity of this minimal CYP11A1 element. Examination of mRNA stability in normal and PCOS theca cells demonstrated that CYP11A1 mRNA half-life increased >2-fold, from approximately 9.22+/−1.62 h in normal cells, to 22.38+/−0.92 h in PCOS cells. Forskolin treatment did not prolong CYP11A1 mRNA stability in either normal or PCOS theca cells. The 5′-UTR of CYP11A1 mRNA confers increased basal mRNA stability in PCOS cells. In conclusion, these studies show that elevated steady state CYP11A1 mRNA abundance in PCOS cells results from increased transactivation of the CYP11A1 promoter and increased CYP11A1 mRNA stability.
doi:10.1371/journal.pone.0048963
PMCID: PMC3498373  PMID: 23155436

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